Nephrology (Carlton, Vic.) · 2026
Targeting TBK1 With GSK8612 Suppresses Kidney and Cardiac Inflammation and Fibrosis in DOCA/Salt Hypertension.
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Huang Jiamin, Rong Wei, Li Ling, Yu Wenqiang, Chen Shuangquan, Xie Haihui, Liang Hua
Аннотация
AIM: To investigate the therapeutic potential of GSK8612, a selective TBK1 inhibitor, against the inflammatory and fibrotic pathological remodeling in the heart and kidneys induced by DOCA/salt hypertension in mice.
METHODS: A salt-sensitive hypertension model was established in male C57BL/6 mice via uninephrectomy followed by DOCA/salt treatment. Hypertensive mice were administered the selective TBK1 inhibitor GSK8612 (1.5 mg/kg, i.p., once every two days) or vehicle for 21 days. Blood pressure was monitored weekly. Renal and cardiac injury were assessed by histopathology, including Hematoxylin and Eosin, Sirius Red, and Masson's trichrome staining. Extracellular matrix deposition was evaluated via Western blot and immunofluorescence. Macrophage-to-myofibroblast transition was determined by F4/80 and α-SMA co-staining. Inflammatory cell infiltration was evaluated by immunohistochemistry, while cytokine mRNA levels were quantified by RT-qPCR.
RESULTS: While GSK8612 treatment showed no significant effect on blood pressure in DOCA/salt-challenged mice, it significantly improved kidney function and attenuated kidney injury compared to DOCA/salt-treated controls. GSK8612 treatment significantly inhibited myofibroblast accumulation and extracellular matrix deposition in the kidneys and reduced infiltration of inflammatory cells. Furthermore, it effectively inhibited macrophage-to-myofibroblast transition in hypertensive nephropathy. Notably, GSK8612 administration also ameliorated DOCA/salt-induced cardiac inflammation and fibrosis, as evidenced by reduced infiltration of F4/80+ macrophages and decreased fibroblast activation.
CONCLUSION: Pharmacological inhibition of TBK1 with GSK8612 confers dual organ protection, attenuating both kidney and heart inflammation and fibrosis in a murine model of salt-sensitive hypertension.
METHODS: A salt-sensitive hypertension model was established in male C57BL/6 mice via uninephrectomy followed by DOCA/salt treatment. Hypertensive mice were administered the selective TBK1 inhibitor GSK8612 (1.5 mg/kg, i.p., once every two days) or vehicle for 21 days. Blood pressure was monitored weekly. Renal and cardiac injury were assessed by histopathology, including Hematoxylin and Eosin, Sirius Red, and Masson's trichrome staining. Extracellular matrix deposition was evaluated via Western blot and immunofluorescence. Macrophage-to-myofibroblast transition was determined by F4/80 and α-SMA co-staining. Inflammatory cell infiltration was evaluated by immunohistochemistry, while cytokine mRNA levels were quantified by RT-qPCR.
RESULTS: While GSK8612 treatment showed no significant effect on blood pressure in DOCA/salt-challenged mice, it significantly improved kidney function and attenuated kidney injury compared to DOCA/salt-treated controls. GSK8612 treatment significantly inhibited myofibroblast accumulation and extracellular matrix deposition in the kidneys and reduced infiltration of inflammatory cells. Furthermore, it effectively inhibited macrophage-to-myofibroblast transition in hypertensive nephropathy. Notably, GSK8612 administration also ameliorated DOCA/salt-induced cardiac inflammation and fibrosis, as evidenced by reduced infiltration of F4/80+ macrophages and decreased fibroblast activation.
CONCLUSION: Pharmacological inhibition of TBK1 with GSK8612 confers dual organ protection, attenuating both kidney and heart inflammation and fibrosis in a murine model of salt-sensitive hypertension.